PROJECT SUMMARY/ABSTRACT The goal of this proposal is to expand and enhance the FDA's opioids systems model to improve and inform the decision- and policy-making necessary to address the opioid crisis. The alarming rise in opioid misuse over the past two-and-a-half decades has resulted in in a public health crisis characterized most prominently by a dramatic increase in drug overdose deaths. This has resulted in a declining life expectancy in the United States over the last three years, representing the first multi-year decrease since 1993. The opioid crisis is not solely a behavioral and/or a biological problem but is also influenced by a complex web of social, mental, and economic factors. Systems modeling is needed to understand this complexity and give proper guidance to policymakers. Without such modeling, interventions may underperform and cause unintended consequences. For example, in the face of the growing opioid crisis, pharmaceutical companies changed the formulation of prescription opioids to deter abuse. However, these abuse-deterrent formulations drove up street prices and, in some cases, drove existing prescription opioid abusers into the use of heroin. Unintended effects like these can be avoided with a careful systems approach. We propose to enhance the depth and breadth of the FDA's systems model by engaging, as a team, 13 individuals with preeminent research in opioids and system dynamics. These experts are thoroughly familiar with the vast body of existing work already done in the field, as well as relevant datasets. Additionally, we have recruited 13 experts who hold leadership roles in law, policy, medicine, and research as advisors. We will first expand the FDA's model, increasing its functional capacity and providing further guidance to those who utilize the model (Aim 1). Then, we will verify the model's ability to provide realistic outputs historically and into the future (Aim 2) and use the expanded model to answer key policy questions and identify the best combination of interventions to combat the opioid crisis (Aim 3). The proposed research will innovatively apply simulation modeling to a problem that would be difficult or impossible to solve with more conventional policy analysis alone. It will result in: 1) a functioning and interactive systems model that can be used to guide policy decisions; 2) insightful policy recommendations at the population level; and 3) multidisciplinary insights to weigh the multiyear benefits and risks of alternative interventions. The knowledge gained will provide new opportunities to improve prescription practices, increase treatment initiation and effectiveness, and decrease OUD, overdoses, and fatalities.